Structure-Based Design of Nonpeptidic HIV Protease Inhibitors from a Cyclooctylpyranone Lead Structure

Abstract

Recently, the novel cyclooctylpyranone HIV protease inhibitor 1 was identified in our labs, and an X-ray structure of this inhibitor complexed with HIV-2 protease was obtained. This crystal structure was used to develop two strategies for creating derivatives of 1 with enhanced enzyme inhibitory activity. The first strategy, substitution on the cyclooctyl ring, met with limited success, but provided some interesting information about the conformationally-flexible cycloocytyl ring on the inhibitors. The second strategy, substitution at the meta position of the aryl ring, was far more successful and generated compounds, such as the carboxamide derivatives 41 (Ki = 3.0 +/- 0.4 nM) and 36 (Ki = 4.0 +/- 0.8 nM), which were significantly more active than the corresponding unsubstituted cycloocytlpyranone 2 (Ki = 11.7 +/- 4.7 nM). An X-ray crystal structure of 36 complexed with HIV-1 protease indicated the increase in binding affinity is most likely due to the additional interactions between the amide substituent and the S3 region of the protease.

Molecular Recognition of Protein−Ligand Complexes: Applications to Drug Design

“…Structure-assisted design based on these screening leads, and the structure of their complex with HIVp has led to the preparation of potent, nonpeptidyl HIVp inhibitors. Two examples of potent compounds resulting from these studies are AP-32 ( K i = 3 nM) and AP-33 ( K i = 3 nM) . (See Figure AP*36.)…”

Structure-Based Design of Nonpeptidic HIV Protease Inhibitors: The Sulfonamide-Substituted Cyclooctylpyranones

“…This activity is comparable to that of the most potent compounds prepared in the carboxamide-substituted series. 12 The saturated analog 8i also had very good activity against the HIV protease (K i ) 3.6 nM).…”

“…For example, the amide derivative 2c (K i ) 4 nM) and the phenyl sulfonamide derivative 8h (K i ) 3.2 nM) have similar enzyme binding affinities, but dramatically different levels of activity in the antiviral assay. 17 For 2c, the ED 50 value in HIV-1 infected H-9 cells was 33 µM, 12 but for 8h, the ED 50 value was only 5.5 µM. In addition, no cytotoxicity for 8h was observed at concentrations up to 30 µM in cell culture.…”

“…2c, K i ) 4 nM) were obtained, but this increase in enzyme binding affinity was not accompanied by a significant increase in antiviral activity. 12 Use of a sulfonamide substituent, however, rather than a carboxamide substituent at the meta position produced analogs which were not only excellent HIV protease inhibitors but also showed significant antiviral activity. 13 This paper will discuss in detail the design and SAR of the cyclooctylpyranone sulfonamides and the selection of a clinical candidate from this promising new class of HIV protease inhibitors.…”

Therapeutic potential of coumarins as antiviral agents

“…The size variation of cycloalkyl ring also provided some interesting information about the binding mode of conformationally-flexible cyclooctyl ring on the inhibitors [22]. Further, they also designed some meta substituted carboxamide derivatives (19 and 20) which were significantly more active than the corresponding unsubstituted cyclooctylpyranone due to its additional hydrogen bonding by the amide group [23]. Substitution of cyclooctylpyranones with a wide variety of arenesulfonamides led to analogues with markedly enhanced antiviral Resolution via chiral HPLC yielded more potent enantiomer having a K i ¼ 0.6 nM and an antiviral IC 50 ¼ 1 mM.…”